U.S. patent application number 12/278587 was filed with the patent office on 2009-06-11 for oxazolidinones containing oxindoles as antibacterial agents.
This patent application is currently assigned to PFIZER INC. Invention is credited to Mikhail Fedorovich Gordeev, Sumithra Gowlugari, Vara Prasad Venkata Nagendra Josyula, Gary Wayne Luehr.
Application Number | 20090149520 12/278587 |
Document ID | / |
Family ID | 38137316 |
Filed Date | 2009-06-11 |
United States Patent
Application |
20090149520 |
Kind Code |
A1 |
Luehr; Gary Wayne ; et
al. |
June 11, 2009 |
OXAZOLIDINONES CONTAINING OXINDOLES AS ANTIBACTERIAL AGENTS
Abstract
The present invention provides a compound of formula (I) or a
pharmaceutically acceptable salt thereof wherein X is
C.sub.1-4alkyl; and Y is H or F. The compounds of the present
invention are useful as antibacterial agents. ##STR00001##
Inventors: |
Luehr; Gary Wayne; (Hayward,
CA) ; Gowlugari; Sumithra; (San Mateo, CA) ;
Gordeev; Mikhail Fedorovich; (Castro Valley, CA) ;
Josyula; Vara Prasad Venkata Nagendra; (Superior Township,
MI) |
Correspondence
Address: |
PFIZER INC;Steve T. Zelson
150 EAST 42ND STREET, 5TH FLOOR - STOP 49
NEW YORK
NY
10017-5612
US
|
Assignee: |
PFIZER INC
|
Family ID: |
38137316 |
Appl. No.: |
12/278587 |
Filed: |
February 6, 2007 |
PCT Filed: |
February 6, 2007 |
PCT NO: |
PCT/IB2007/000284 |
371 Date: |
August 7, 2008 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
60771570 |
Feb 8, 2006 |
|
|
|
Current U.S.
Class: |
514/376 ;
548/229 |
Current CPC
Class: |
A61P 31/04 20180101;
C07D 413/14 20130101 |
Class at
Publication: |
514/376 ;
548/229 |
International
Class: |
A61K 31/422 20060101
A61K031/422; C07D 263/18 20060101 C07D263/18; A61P 31/04 20060101
A61P031/04 |
Claims
1. A compound of formula I ##STR00013## or a pharmaceutically
acceptable salt thereof wherein R is H or F; and R.sup.1 is
C.sub.1-4alkyl.
2. A compound of claim 1 which is (1)
(R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(1-isopropyl-2-oxoindolin-5-yl)ox-
azolidin-2-one, (2)
(R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(1-ethyl-2-oxoindolin-5-yl)oxazol-
idin-2-one, or (3)
(R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(1-methyl-2-oxoindolin-5-yl)oxazo-
lidin-2-one.
3. A pharmaceutical composition comprising a compound of claim 1 or
a pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier.
4. A method for treating bacteria infections comprising
administering to a mammal being treated a pharmaceutically
effective amount of the compound of claim 1.
5. The method of claim 4 wherein the compound of claim 1 is
administered orally, parenterally, topically, rectally, or
intranasally.
6. The method of claim 4 wherein said compound is administered in
an amount of from about 0.1 to about 100 mg/kg of body
weight/day.
7. The method of claim 4 wherein said compound is administered in
an amount of from about 1 to about 50 mg/kg of body weight/day.
8. The bacteria infection of claim 4 which is ear infections, eye
infections, respiratory tract infections, skin and skin structure
infections, bacterial endocarditis, osteomyelitis, endocarditis or
diabetic foot.
9. The bacteria infection of claim 4 which is caused by
gram-positive bacteria, gram negative bacteria, anaerobic
organisms, and acid-fast organisms.
10. The bacteria infection of claim 4 which is caused by bacteria
comprising staphylococci, streptococci, Enterococci, Haemophilus,
Moraxella, bacteroides, clostridia, Mycobacteria, or Chlamydia.
11. The bacteria of claim 10 wherein staphylococci is S. aureus and
S. epidermidis; wherein streptococci is S. pneumoniae of S.
pyogenes; wherein Enterococci is E. faecalis; wherein Haemophilus
is H. influenzae; wherein Moraxella is M. catarrhalis; and wherein
Mycobacteria is M. tuberculosis; or Mycobacterium avium.
12. The bacteria infections of claim 4 which is caused by
multi-drug resistant S. aureus.
Description
FIELD OF INVENTION
[0001] The present invention relates to novel oxindole derivatives
of oxazolidinones, pharmaceutical compositions thereof, methods for
their use, and methods for preparation. These compounds have potent
activities against gram-positive bacteria.
BACKGROUND OF THE INVENTION
[0002] Antibacterial resistance is a global clinical and public
health problem that has emerged with alarming rapidity in recent
years and undoubtedly will increase in the near future. Resistance
is a problem in the community as well as in health care settings,
where transmission of bacteria is greatly amplified. Because
multiple drug resistance is a growing problem, physicians are now
confronted with infections for which there is no effective therapy.
As result, structurally novel antibacterials with a new mode of
action have become increasingly important in the treatment of
bacterial infections.
[0003] Among newer antibacterial agents, oxazolidinone compounds
are the most recent synthetic class of antimicrobials active
against a number of pathogenic microorganisms. This invention
provides novel oxindole derivatives of oxazolidinones, and their
preparation.
INFORMATION DISCLOSURE
[0004] PCT publication WO 0181350 discloses oxazolidinone
derivatives containg an N-linked heterocycle as antibacterial
agents.
[0005] PCT publication WO 03072575 discloses oxazolidinone
derivatives incorporating a nitrogen containing 5-membered ring and
their use as antibacterial agents.
[0006] PCT publication WO 2004/074282 discloses antibacterial
indolone oxazolidinones.
SUMMARY OF THE INVENTION
[0007] The present invention provides a compound of formula I
##STR00002##
or a pharmaceutically acceptable salt thereof wherein:
[0008] R is H or F; and R.sup.1 is C.sub.1-4alkyl.
[0009] In another aspect, the present invention also provides:
[0010] a pharmaceutical composition which comprises a
pharmaceutically acceptable carrier and an effective amount of a
compound of formula I,
[0011] a method for treating gram-positive microbial infections in
a mammal by administering to the subject in need a therapeutically
effective amount of a compound of formula I or a pharmaceutically
acceptable salt thereof, and
[0012] a use of a compound of formula I or a pharmaceutically
acceptable salt thereof to prepare a medicament for treating
gram-positive microbial infections.
[0013] The invention may also provide novel intermediates and novel
processes that are useful for preparing compounds of formula I.
DETAILED DESCRIPTION OF THE INVENTION
[0014] Unless otherwise stated, the following terms used in the
specification and claims have the meanings given below:
[0015] The carbon atom content of various hydrocarbon-containing
moieties is indicated by a prefix designating the minimum and
maximum number of carbon atoms in the moiety, i.e., the prefix
C.sub.i-j indicates a moiety of the integer "i" to the integer "j"
carbon atoms, inclusive. Thus, for example, C.sub.1-4 alkyl refers
to alkyl of one to four carbon atoms, inclusive.
[0016] The term alkyl refers to both straight and branched groups,
but reference to an individual radical such as "propyl" embraces
only the straight chain radical, a branched chain isomer such as
"isopropyl" being specifically referred to.
[0017] The term "a pharmaceutically acceptable salt" of a compound
means a salt that is pharmaceutically acceptable and that possesses
the desired pharmacological activity of the parent compound. Such
salts include:
[0018] (1) acid addition salts, formed with inorganic acids such as
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid, and the like; or formed with organic acids such as
acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic
acid, glycolic acid, pyruvic acid, lactic acid, malonic acid,
succinic acid, malic acid, maleic acid, fumaric acid, tartaric
acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid,
cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic
acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,
benzenesulfonic acid, 4-chlorobenzenesulfonic acid,
2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic
acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid,
glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic
acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary
butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic
acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic
acid, and the like; or
[0019] (2) salts formed when an acidic proton present in the parent
compound either is replaced by a metal ion, e.g., an alkali metal
ion, an alkaline earth ion, or an aluminum ion; or coordinates with
an organic base such as ethanolamine, diethanolamine,
triethanolamine, tromethamine, N-methylglucamine, and the like.
[0020] The term "pharmaceutically acceptable carrier" means a
carrier that is useful in preparing a pharmaceutical composition
that is generally safe, non-toxic and neither biologically nor
otherwise undesirable, and includes a carrier that is acceptable
for veterinary use as well as human pharmaceutical use. "A
pharmaceutically acceptable carrier" as used in the specification
and claims includes both one and more than one such carrier.
[0021] The term "mammal" refers to human or warm-blooded animals
including livestock and companion animals.
[0022] The term "optional" or "optionally" means that the
subsequently described event or circumstance may, but need not,
occur, and that the description includes instances where the event
or circumstance occurs and instances in which it does not.
[0023] Compounds that have the same molecular formula but differ in
the nature or sequence of bonding of their atoms or the arrangement
of their atoms in space are termed "isomers". Isomers that differ
in the arrangement of their atoms in space are termed
"stereoisomers".
[0024] Stereoisomers that are not mirror images of one another are
termed "diastereomers" and those that are non-superimposable mirror
images of each other are termed "enantiomers". When a compound has
an asymmetric center, for example, it is bonded to four different
groups, a pair of enantiomers is possible. An enantiomer can be
characterized by the absolute configuration of its asymmetric
center and is described by the R- and S-sequencing rules of Cahn
and Prelog, or by the manner in which the molecule rotates the
plane of polarized light and designated as dextrorotatory or
levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral
compound can exist as either individual enantiomer or as a mixture
thereof. A mixture containing equal proportions of the enantiomers
is called a "racemic mixture".
[0025] The compounds of this invention may possess one or more
asymmetric centers; such compounds can therefore be produced as
individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless
indicated otherwise, the description or naming of a particular
compound in the specification and claims is intended to include
both individual enantiomers and mixtures, racemic or otherwise,
thereof. The methods for the determination of stereochemistry and
the separation of stereoisomers are well-known in the art (see
discussion in Chapter 4 of "Advanced Organic Chemistry", 4th
edition J. March, John Wiley and Sons, New York, 1992).
[0026] The term "treating" or "treatment" of a disease includes:
(1) preventing the disease, i.e. causing the clinical symptoms of
the disease not to develop in a mammal that may be exposed to or
predisposed to the disease but does not yet experience or display
symptoms of the disease; (2) inhibiting the disease, i.e.,
arresting or reducing the development of the disease or its
clinical symptoms; or (3) relieving the disease, i.e., causing
regression of the disease or its clinical symptoms.
[0027] The term "therapeutically effective amount" means the amount
of a compound that, when administered to a mammal for treating a
disease, is sufficient to effect such treatment for the disease.
The "therapeutically effective amount" will vary depending on the
compound, the disease and its severity and the age, weight, etc.,
of the mammal to be treated.
[0028] The term "leaving group" has the meaning conventionally
associated with it in synthetic organic chemistry i.e., an atom or
group capable of being displaced by a nucleophile and includes
halogen, alkylsulfonyloxy, ester, or amino such as chloro, bromo,
iodo, mesyloxy, tosyloxy, trifluorosulfonyloxy, methoxy,
N,O-dimethylhydroxyl-amino, and the like.
[0029] The compounds of the present invention are generally named
according to the IUPAC or CAS nomenclature system.
[0030] Abbreviations which are well known to one of ordinary skill
in the art may be used (e.g. "Ph" for phenyl, "Me" for methyl, "Et"
for ethyl, "h" for an hour or hours and "rt" for room
temperature).
[0031] Specific and preferred values listed below for radicals,
substituents, and ranges, are for illustration only; they do not
exclude other defined values or other values within defined ranges
for the radicals and substituents.
[0032] Specifically, X is methyl, ethyl, propyl, isopropyl, butyl,
iso-butyl, sec-butyl, and their isomeric forms thereof.
[0033] Specifically Y is H.
[0034] Examples of the present invention include: [0035]
(1)-5-(1H-1,2,3-triazol-1-yl)methyl)-3-(1-isopropyl-2-oxoindolin-5-yl)oxa-
zolidin-2-one, [0036]
(2)-5-(1H-1,2,3-triazol-1-yl)methyl)-3-(1-ethyl-2-oxoindolin-5-yl)oxazoli-
din-2-one, or [0037]
(3)-5-(1H-1,2,3-triazol-1-yl)methyl)-3-(1-methyl-2-oxoindolin-5-yl)oxazol-
idin-2-one.
[0038] Compounds of this invention can be prepared in accordance
with one or more of the Schemes discussed below. All of the
starting materials are either commercially available or can be
prepared by procedures that would be well known to one of ordinary
skill in organic chemistry. The variables used in the Schemes are
as defined below, or as in the summary of the invention or
claims.
##STR00003##
[0039] Scheme I illustrates the construction of an oxazolidinone
ring bearing a 1,2,3-triazole-1-yl methyl group at the C-5
position. The aniline intermediate 1a is first converted to an aryl
carbamate using standard procedures that are well known to those
skilled in the art, for example using benzyl chloroformate and
pyridine in dichloromethane. The aryl carbamate 1b is reacted with
(S)-(3-chloro-2-hydroxy-propyl)-carbamic acid tert-butyl ester
(prepared as described in U.S. Pat. No. 6,833,453). The reaction is
performed in the presence of an organic base such as lithium
tert-butoxide, in a polar organic solvent such as dimethylformamide
or acetonitrile, at temperatures of about 0.degree. C. to
25.degree. C. The product may be used as collected or may first be
purifed using conventional techniques such as preparative TLC or
HPLC, chromatography, precipitation, crystallization and the like.
The product of this reaction is intermediate 1c bearing a
tert-butyl carbamate (Boc protected amine) at the C-5 position.
Intermediate 1c is deprotected by treatment with acids such as
hydrochloric acid or trifluoracetic acid. If less harsh conditions
are required, treatment with trimethylsilyltrifluoromethane
sulfonate and 2,6-lutidine (as described by Ohfune, Y. and
Sakaitani, M. J. Org. Chem. 1990, 55, 870-876) is also effective.
Finally, amine 1d is reacted with an appropriately substituted
arenesulfonyl hydrazone according to the methods of Ichikawa (Chem.
Pharm. Bull., 2000, 48, 1947-1953) and Sakai (Bull. Chem. Soc.
Jpn., 1986, 59, 179-184) to provide triazole oxazolidinone 1e
werein R' is hydrogen or other substituents such as halo, alkyl,
and etc.
##STR00004##
[0040] Alternatively as described in Scheme II, 2a is reacted with
a Boc protected (S)-glycidylamine (prepared following methods
described in International Patent Publication No. WO 02/32857) in
the presence of a Lewis acid such as lithium triflate in a suitable
solvent such as acetonitrile at a suitable temperature, typically
in the range from 20.degree. C. to 110.degree. C. to provide 2b.
The amino alcohol 2b can then be ring closed to give the aryl
oxazolidinones 2c using methods known to one skilled in the art.
For instance, treatment of structures 2b with
1,1'-carbonyldiimidazole in a solvent such as acetonitrile or
tetrahydrofuran at an appropriate temperature, typically in a range
of 20.degree. C. to 60.degree. C., or with phosgene in a solvent
such as toluene or methylene chloride, or mixtures thereof, in the
presence of a base such as triethylamine at an appropriate
temperature, typically in a range from -10.degree. C. to 25.degree.
C., affords 2c. Oxazolidinone 2c may be deprotected and converted
to triazole 2e following methods described in Scheme I.
##STR00005##
[0041] In another embodiment of the reaction process described in
Scheme III, carbamate 3a is converted to the azido oxazolidinone 3c
following the sequence of chemical transformations described by
Brickner (J. Med. Chem., 1996, 39, 673-679). Cycloaddition of the
intermediate azido compound with norbornadiene in a suitable
solvent, such as dioxane at reaction temperatures in the range of
about 50.degree. C. to about 100.degree. C. affords the
1,2,3-triazolyl derivative 3d (R'=H). Alternatively, a variety of
other substituted triazoles (R'=Me, Cl, F, --OH, --CH.sub.2OH,
--CH.sub.2CN, --CN, --C.dbd.CH, --NH.sub.2) may be prepared via
cycloaddition in the presence of Cu(I) catalysis as described by
Rostovtsec (Angew. Chem. Int. Ed., 2002, 41, 2596-2599) and
subsequent chemical group modification by known methods when
necessary.
##STR00006##
[0042] Scheme IV exemplifies another route to prepare
oxazolidinones 4e via oxidation of indole precursors. Appropriately
substituted 5-nitroindole 4a is reacted with an appropriate
alkylating agent such as an alkyl halide, tosylate or sulfate in
the presence of a strong base such as sodium hydride in a polar
aprotic solvent such as dimethylformamide to provide N-alkylindole
4b. 4b is reduced under a variety of known conditions including
catalytic hydrogenation over a noble metal catalyst or a Raney
Nickel catalyst, a dissolving metal reduction such as iron and
ammonium chloride in aqueous ethanol or iron in acetic acid to
provide aniline 4c. 4c is converted to the aryl carmbamate 4d, the
azido compound 4f, and the triazole oxazolidinone 4g following the
sequence of chemical transformations described in the previous
scheme. N-Alkylindole 4g is further oxidized to the requisite
oxindole 4h by a variety of known methods (e.g. DMSO/HCl, NBS).
##STR00007##
[0043] Triazole oxazolidinones 5e may also be prepared following
the route detailed in Scheme V. Oxindole amine 5a is reacted with
the conmmercially available (R)-(-)-epichlorohydrin either neat or
in a suitable inert solvent such as acetonitrile or isopropanol at
temperatures between ambient to about 100.degree. C. to afford 5b.
A Lewis acid catalyst such as lithium triflate may be added.
Aminoalcohol 5b can then be ring closed to give the aryl
oxazolidinones 5c using methods known to one skilled in the art.
For instance, treatment of structures 5b with
1,1'-carbonyldiimidazole in a solvent such as acetonitrile or
tetrahydrofuran at an appropriate temperature, typically in a range
of 20.degree. C. to 60.degree. C., or with phosgene in a solvent
such as toluene or methylene chloride, or mixtures thereof, in the
presence of a base such as triethylamine at an appropriate
temperature, typically in a range from -10.degree. C. to 25.degree.
C., affords 5c. Reaction of the chloro oxazolidinone 5c with an
azide source such as sodium azide in a suitable solvent such as
dimethylformamide at temperatures between ambient to about
75.degree. C. provides 5d. Azido oxazolidinone 5d may be converted
to triazole oxazolidinones 5e by methods described previously in
Scheme III.
##STR00008##
[0044] Oxindole intermediates may be prepared according to the
method of Scheme VII. Isatin 7a, obtained commercially or
conveniently prepared according to the methods of Gassman described
in J. Org. Chem. 1977, 42, 1344 and U.S. Pat. Nos. 4,188,325 and
4,2527,23, is treated with an alkylating agent, e.g., iodomethane,
iodoethane, or iodopropane, in the presence of a suitable base
(e.g. an amine base such as triethylamine or
di-iso-propylethylamine or lithium, sodium, potassium or cesium
carbonate) in a suitable organic solvent (e.g. DMF, THF, DMSO,
dioxane or acetonitrile) at a temperature between 0.degree. C. and
65.degree. C. to afford N-alkylated isatin 7b. Isatins 7b may be
reduced to 1,3-dihydroindol-2-ones 7c by using red phosphorous and
iodic acid, by use of hydrogen sulfide in pyridine/co-solvent
mixture, or by the Wolf-Kishner reaction. The most convenient
procedure involves heating isatin 7b in neat hydrazine hydrate at
reflux in the absence of any additional base.
1,3-Dihydroindol-2-one 7c is nitrated regioselectively using
methods known to one skilled in the art (e.g., nitric acid in
concentrated sulfuric acid or acetic acid, or sodium nitrate in
trifluoroacetic acid at temperatures between -20.degree. C. and
25.degree. C.). 5-Nitrooxindole 7d is then reduced by dissolving
metal reduction (e.g., iron and ammonium chloride in ethanol/water)
or catalytic hydrogenation to provide the 5-aminooxindole 7e.
##STR00009##
[0045] Alternatively, known 5-nitroisatins 8a are treated with an
appropriate alkylating agent, e.g., iodomethane, iodoethane, or
iodopropane, in the presence of a suitable base base (e.g. an amine
base such as triethylamine or di-iso-propylethylamine or lithium,
sodium, potassium or cesium carbonate) in a suitable organic
solvent (e.g. DMF, TF, DMSO, dioxane or acetonitrile) at a
temperature between 0.degree. C. and 65.degree. C. to afford
N-alkylated isatin 8b. Isatin 8b may be reduced in one step to the
requisite 5-aminooxindole 8c by heating in neat hydrazine hydrate
at reflux temperatures or by catalytic hydrogenation.
##STR00010##
[0046] In another route exemplified by Scheme IX, an appropriately
substituted 2-halo-5-nitrophenylacetic acid 9a (e.g., preferably
2-fluoro-5-nitrophenylacetic acid) is treated with ammonia or an
optionally substituted amine (R.sup.1NH.sub.2) in a suitable
solvent such as DMSO or acetonitrile at temperatures between
35.degree. C. and 85.degree. C. to afford 9b (R.sup.1=H or
optionally substituted alkyl). Aniline 9b is treated with a strong
acid such as HCl, H.sub.2SO.sub.4, or TFA to effect cyclization to
the requisite 5-nitrooxindole 9c. 5-Nitrooxindole 9c is then
reduced by dissolving metal reduction (e.g., iron and ammonium
chloride in ethanoVwater) or catalytic hydrogenation to provide the
5-aminooxindole 9d.
Medical and Veterinary Uses
[0047] The compound of the present invention may be used for the
treatment of infectious, Gram-positive bacterial infections caused
by a variety of bacterial organisms, including those that require
long-term therapy (>28 days).
[0048] Examples of the bacterial organisms include gram-positive
bacteria such as multiple resistant staphylococci, for example S.
aureus and S. epidermidis; multiple resistant streptococci, for
example S. pneumoniae and S. pyogenes; and multiple resistant
Enterococci, for example E. faecalis; gram negative aerobic
bacteria such as Haemophilus, for example H. influenzae and
Moraxella, for example M. catarrhalis; as well as anaerobic
organisms such as bacteroides and clostridia species, and acid-fast
organisms such as Mycobacteria, for example M. tuberculosis; and/or
Mycobacterium avium. Other examples include Escherichia, for
example E. coli. intercellular microbes, for example Chlamydia and
Rickettsiae.
[0049] Examples of infections that may be treated with the compound
of the present invention include central nervous system infections,
external ear infections, infections of the middle ear, such as
acute otitis media, infections of the cranial sinuses, eye
infections, infections of the oral cavity, such as infections of
the teeth, gums and mucosa, upper respiratory tract infections,
lower respiratory tract infections, genitourinary infections,
gastrointestinal infections, gynecological infections, septicemia,
bone and joint infections, skin and skin structure infections,
bacterial endocarditis, burns, antibacterial prophylaxis of
surgery, and antibacterial prophylaxis in immunosuppressed
patients, such as patients receiving cancer chemotherapy, or organ
transplant patients. Specifically, infectious diseases that may be
treated with the compound of the present invention are
gram-positive infections such as osteomyelitis, endocarditis and
diabetic foot.
Antibacterial Activity
[0050] The in vitro antibacterial activity of the compounds of the
present invention may be assessed by following procedures
recommended in (1) National Committee for Clinical Laboratory
Standards (January 2003), Methods for dilution antimicrobial tests
for bacteria that grow aerobically, Approved Standard (6.sup.th
ed), M7-A6, NCCLS, Wayne, Pa.; (2) National Committee for Clinical
Laboratory Standards (March 2001), Methods for antimicrobial
susceptibility testing of anaerobic bacteria, Approved Standard
(5.sup.th ed), M11-A4, NCCLS, Wayne, Pa.; (3) National Committee
for Clinical Laboratory Standards (Jan. 2003), MIC testing
supplemental tables, M100-S13 (for use with M7-A6), NCCLS, Wayne,
Pa.; and (4) Murray P R, Baron E J, Jorgensen J H, et al. Manual of
Clinical Microbiology (8.sup.th ed) Washington, D.C.: American
Society for Microbiology Press, 2003. The antibacterial activity
can be presented in the form of MIC value. The MIC value is the
lowest concentration of drug, which prevented macroscopically
visible growth under the conditions of the test. Table 1 lists the
in vitro antibacterial activity of the present invention.
TABLE-US-00001 TABLE 1 Results of in vitro antibacterial activity
MIC.sub.s (.mu.g/mL) S. aureus S. pneumoniae E. faecalis Example
No. UC-76 SA-1 SV1 SP-3 MGH-2 EF 1-1 1 8 8 8 2 4 4 8
Pharmaceutical Salts
[0051] The compound of formula I may be used in its native form or
as a salt. In cases where forming a stable nontoxic acid or base
salt is desired, administration of the compound as a
pharmaceutically acceptable salt may be appropriate. Examples of
pharmaceutically acceptable salts of the present invention include
inorganic salts such as hydrochloride, hydrobromide, sulfate,
nitrate, bicarbonate, carbonate salts, and organic salts such as
tosylate, methanesulfonate, acetate, citrate, malonate, tartarate,
succinate, benzoate, ascorbate, etoglutarate, and glycerophosphate.
Pharmaceutically acceptable salts may be obtained using standard
procedures well known in the art, for example, reacting a
sufficiently basic compound such as an amine with a suitable acid
affording a physiologically acceptable anion. Alkali metal (for
example, sodium, potassium or lithium) or alkaline earth metal (for
example calcium) salts of carboxylic acids can also be made.
[0052] Routes of Administration
[0053] In therapeutic use for treating, or combating, bacterial
infections in a mammal (i.e. human and animals), a compound of the
present invention or its pharmaceutical compositions can be
administered orally, parenterally, topically, rectally,
transmucosally, or intestinally.
[0054] Parenteral administrations include indirect injections to
generate a systemic effect or direct injections to the afflicted
area. Examples of parenteral administrations are subcutaneous,
intravenous, intramuscular, intradermal, intrathecal, intraocular,
intranasal, intravetricular injections or infusions techniques.
[0055] Topical administrations include the treatment of infectious
areas or organs readily accessibly by local application, such as,
for example, eyes, ears including external and middle ear
infections, vaginal, open wound, skins including the surface skin
and the underneath dermal structures, or other lower intestinal
tract. It also includes transdermal delivery to generate a systemic
effect.
[0056] The rectal administration includes the form of
suppositories.
[0057] The transmucosal administration includes nasal aerosol or
inhalation applications.
[0058] The preferred routes of administration are oral and
parenteral.
Composition/Formulation
[0059] Pharmaceutical compositions of the present invention may be
manufactured by processes well known in the art, e.g., by means of
conventional mixing, dissolving, granulation, dragee-making,
levigating, emulsifying, encapsulating, entrapping, lyophilizing
processes or spray drying.
[0060] Pharmaceutical compositions for use in accordance with the
present invention may be formulated in conventional manner using
one or more physiologically acceptable carriers comprising
excipients and auxiliaries, which facilitate processing of the
active compound into preparations, which can be used
pharmaceutically. Proper formulation is dependent upon the route of
administration chosen.
[0061] For oral administration, the compound can be formulated by
combining the active compound with pharmaceutically acceptable
carriers well known in the art. Such carriers enable the compound
of the invention to be formulated as tablets, pills, lozenges,
dragees, capsules, liquids, solutions, emulsions, gels, syrups,
slurries, suspensions and the like, for oral ingestion by a
patient. A carrier can be at least one substance which may also
function as a diluent, flavoring agent, solubilizer, lubricant,
suspending agent, binder, tablet disintegrating agent, and
encapsulating agent. Examples of such carriers or excipients
include, but are not limited to, magnesium carbonate, magnesium
stearate, talc, sugar, lactose, sucrose, pectin, dextrin, mannitol,
sorbitol, starches, gelatin, cellulosic materials, low melting wax,
cocoa butter or powder, polymers such as polyethylene glycols and
other pharmaceutical acceptable materials.
[0062] Dragee cores are provided with suitable coatings. For this
purpose, concentrated sugar solutions may be used which may
optionally contain gum arabic, talc, polyvinyl pyrrolidone,
carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer
solutions, and suitable organic solvents or solvent mixtures.
Dyestuffs or pigments may be added to the tablets or dragee
coatings for identification or to characterize different
combinations of active compound doses.
[0063] Pharmaceutical compositions, which can be used orally,
include push-fit capsules made of gelatin, as well as soft, sealed
capsules made of gelatin and a plasticizer, such as glycerol or
sorbitol. The push-fit capsules can contain the active ingredients
in admixture with a filler such as lactose, a binder such as
starch, and/or a lubricant such as talc or magnesium stearate and,
optionally, stabilizers. In soft capsules, the active compound may
be dissolved or suspended in suitable liquids, such as fatty oils,
liquid paraffin, liquid polyethylene glycols, cremophor, capmul,
medium or long chain mono-, di- or triglycerides. Stabilizers may
be added in these formulations, also.
[0064] Liquid form compositions include solutions, suspensions and
emulsions. For example, there may be provided solutions of the
compound of this invention dissolved in water and water-propylene
glycol and water-polyethylene glycol systems, optionally containing
suitable conventional coloring agents, flavoring agents,
stabilizers and thickening agents.
[0065] The compound may also be formulated for parenteral
administration, e.g., by injections, bolus injection or continuous
infusion. Formulations for parenteral administration may be
presented in unit dosage form, e.g., in ampoules or in multi-dose
containers, with an added preservative. The compositions may take
such forms as suspensions, solutions or emulsions in oily or
aqueous vehicles, and may contain formulating materials such as
suspending, stabilizing and/or dispersing agents.
[0066] For injection, the compound of the invention may be
formulated in aqueous solution, preferably in physiologically
compatible buffers or physiological saline buffer. Suitable
buffering agents include tri-sodium orthophosphate, sodium
bicarbonate, sodium citrate, N-methylglucamine, L(+)-lysine and
L(+)-arginine.
[0067] Parenteral administrations also include aqueous solutions of
a water soluble form, such as, without limitation, a salt, of the
active compound. Additionally, suspensions of the active compound
may be prepared in a lipophilic vehicle. Suitable lipophilic
vehicles include fatty oils such as sesame oil, synthetic fatty
acid esters such as ethyl oleate and triglycerides, or materials
such as liposomes. Aqueous injection suspensions may contain
substances, which increase the viscosity of the suspension, such as
sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally,
the suspension may also contain suitable stabilizers and/or agents
that increase the solubility of the compound to allow for the
preparation of highly concentrated solutions.
[0068] Alternatively, the active ingredient may be in powder form
for constitution with a suitable vehicle, e.g., sterile,
pyrogen-free water, before use.
For suppository administration, the compound may also be formulated
by mixing the agent with a suitable non-irritating excipient, which
is solid at room temperature but liquid at rectal temperature and
therefore will melt in the rectum to release the drug. Such
materials include cocoa butter, beeswax and other glycerides.
[0069] For administration by inhalation, compound of the present
invention can be conveniently delivered through an aerosol spray in
the form of solution, dry powder, or suspensions. The aerosol may
use a pressurized pack or a nebulizer and a suitable propellant. In
the case of a pressurized aerosol, the dosage unit may be
controlled by providing a valve to deliver a metered amount.
Capsules and cartridges of, for example, gelatin for use in an
inhaler may be formulated containing a power base such as lactose
or starch.
[0070] For topical applications, the pharmaceutical composition may
be formulated in a suitable ointment containing the active
component suspended or dissolved in one or more carriers. Carriers
for topical administration of the compounds of this invention
include, but are not limited to, mineral oil, liquid petrolatum,
white petrolatum, propylene glycol, polyoxyethylene,
polyoxypropylene compound, emulsifying wax and water.
Alternatively, the pharmaceutical compositions can be formulated in
a suitable lotion such as suspensions, emulsion, or cream
containing the active components suspended or dissolved in one or
more pharmaceutically acceptable carriers. Suitable carriers
include, but are not limited to, mineral oil, sorbitan monosterate,
polysorbate 60, cetyl esters wax, ceteary alcohol,
2-octyldodecanol, benzyl alcohol and water.
[0071] For ophthalmic and otitis uses, the pharmaceutical
compositions may be formulated as micronized suspensions in
isotonic, pH adjusted sterile saline, or preferably, as solutions
in isotonic, pH adjusted sterile saline, either with or without a
preservative such as a benzylalkonium chloride. Alternatively, for
ophthalmic uses, the pharmaceutical compositions may be formulated
in an ointment such as petrolatum.
[0072] In addition to the formulations described previously, the
compound may also be formulated as depot preparations. Such long
acting formulations may be in the form of implants. A compound of
this invention may be formulated for this route of administration
with suitable polymers, hydrophobic materials, or as a sparing
soluble derivative such as, without limitation, a sparingly soluble
salt.
[0073] Additionally, the compound may be delivered using a
sustained-release system. Various sustained-release materials have
been established and are well known by those skilled in the art.
Sustained-release capsules may, depending on their chemical nature,
release the compound for 24 hours or for up to several days.
Dosage
[0074] Pharmaceutical compositions suitable for use in the present
invention include compositions wherein the active ingredients are
contained in an amount sufficient to achieve the intended purpose,
i.e., the treatment or prevent of infectious diseases. More
specifically, a therapeutically effective amount means an amount of
compound effective to prevent, alleviate or ameliorate symptoms of
disease or prolong the survival of the subject being treated.
[0075] The quantity of active component, that is the compound of
this invention, in the pharmaceutical composition and unit dosage
form thereof may be varied or adjusted widely depending upon the
manner of administration, the potency of the particular compound
and the desired concentration. Determination of a therapeutically
effective amount is well within the capability of those skilled in
the art. Generally, the quantity of active component will range
between 0.5% to 90% by weight of the composition.
[0076] Generally, a therapeutically effective amount of dosage of
active component will be in the range of about 0.1 to about 400
mg/kg of body weight/day, more preferably about 1.0 to about 50
mg/kg of body weight/day. It is to be understood that the dosages
may vary depending upon the requirements of each subject and the
severity of the bacterial infection being treated. In average, the
effective amount of active component is about 200 mg to 800 mg and
preferable 600 mg per day.
[0077] The desired dose may conveniently be presented in a single
dose or as divided doses administered at appropriate intervals, for
example, as two, three, four or more sub-doses per day. The
sub-dose itself may be further divided, e.g., into a number of
discrete loosely spaced administrations; such as multiple
inhalations from an insufflator or by application of a plurality of
drops into the eye.
[0078] Also, it is to be understood that the initial dosage
administered may be increased beyond the above upper level in order
to rapidly achieve the desired plasma concentration. On the other
hand, the initial dosage may be smaller than the optimum and the
daily dosage may be progressively increased during the course of
treatment depending on the particular situation. If desired, the
daily dose may also be divided into multiple doses for
administration, e.g., two to four times per day.
[0079] In cases of local administration or selective uptake, the
effective local concentration of the drug may not be related to
plasma concentration and other procedures know in the art may be
used to determine the desired dosage amount.
EXAMPLES
[0080] In the discussion above and in the examples below, the
following abbreviations have the following meanings. If an
abbreviation is not defined, it has its generally accepted meaning.
[0081] bm=broad multiplet [0082] BOC=tert-butoxycarbonyl [0083]
bd=broad doublet [0084] bs=broad singlet [0085]
CDI=1,1O-carbodiimidazole [0086] d=doublet [0087] dd=doublet of
doublets [0088] dq=doublet of quartets [0089] dt=doublet of
triplets [0090] DMF=dimethylformamide [0091]
DMAP=dimethylaminopyridine [0092] DMSO=dimethyl sulfoxide [0093]
eq.=equivalents [0094] g=grams [0095] h=hours [0096] HPLC=high
pressure liquid chromatography [0097]
HATU=N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-yl-methylene]--
N-methylmethanaminium hexafluorophosphate N-oxide [0098] LG leaving
group [0099] m=multiplet [0100] M=molar [0101] M %=mole percent
[0102] max=maximum [0103] meq=milliequivalent [0104] mg=milligram
[0105] mL=milliliter [0106] mm=millimeter [0107] mmol=millimol
[0108] q=quartet [0109] s=singlet [0110] t or tr=triplet [0111]
TBS=tributylsilyl [0112] TFA=trifluoroacetic acid [0113]
THF=tetrahydrofuran [0114] TLC thin layer chromatography [0115]
p-TLC=preparative thin layer chromatography [0116] .mu.L=microliter
[0117] N=normality [0118] MeOH=methanol [0119] DCM=dichloromethane
[0120] HCl=hydrochloric acid [0121] ACN=acetonitrile [0122] MS=mass
spectrometry [0123] rt=room temperature [0124] EtOAc=ethyl acetate
[0125] EtO=ethoxy [0126] Ac=acetate [0127]
NMP=1-methyl-2-pyrrolidinone [0128] .mu.L=microliter [0129]
J=coupling constant [0130] NMR=Nuclear magnetic resonance [0131]
MHz=megahertz [0132] Hz=hertz [0133] m/z=mass to charge ratio
[0134] min=minutes [0135] Boc=tert-butoxycarbonyl [0136]
CBZ=benzyloxycarbonyl [0137] DCC=1,3-dicyclohexylcarbodimide [0138]
PyBop=benzotriazole-1-yl-oxy-trispyrrolidinophosphonium
hexafluorophosphate
Example 1
Preparation of
(R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(1-isopropyl-2
oxoindolin-5-yl)oxazolidin-2-one
##STR00011##
[0139] Method A
[0140] Step 1. Preparation of 1-isopropyl-5-nitro-1H-indole.
[0141] 5-Nitro-1H-indole (2.00 g, 0.012 mol) in dimethylformamide
(8 mL) is added to a suspension of sodium hydride (60% in mineral
oil, 0.71 g, 0.015 mol) in dimethylformamide (30 mL) at 0.degree.
C. After 30 min at 0.degree. C., isopropyl iodide (1.35 mL, 0.013
mol) is added and the mixture stirred for 6 h at room temperature.
The reaction is diluted with water and extracted with ethyl
acetate. The organic layer is separated, washed with water and
brine, dried (Na.sub.2SO.sub.4) and evaporated. The residue is
purified by flash column chromatography to provide the title
compound. HPLC(SYMMETRY C.sub.18 3.5 .mu.M, 4.6.times.30 mm column;
gradient elution 2%-98% MeCN with 0.1% TFA over 10 min; 2 mL/min
rate): retention time=5.862 min; MS for
C.sub.11H.sub.12N.sub.2O.sub.2 (m/z) 203.0 (M-H).sup.+.
Step 2. Preparation of 1-isopropyl-1H-indol-5-amine.
[0142] Iron powder (0.549 g, 0.01 mol) is added portionwise to
1-isopropyl-5-nitro-1H-indole (0.5 g, 0.0024 mol) and ammonium
chloride (1.309 g, 0.0025 mol) in ethanol (40 mL) and water (20 mL)
at 90.degree. C. The mixture is stirred vigorously and heated for 1
hour, allowed to cool, and diluted with dichloromethane (500 mL).
The mixture is filtered through celite, washed with water and
brine, dried (Na.sub.2SO.sub.4) and evaporated to the title
compound. HPLC(SYMMETRY C.sub.18 3.5 .mu.M, 4.6.times.30 mm column;
gradient elution 2%-98% MeCN with 0.1% TFA over 10 min; 2 mL/min
rate): retention time=3.208 min; MS for C.sub.11H.sub.14N.sub.2
((m/z) 174.2 (M+H).sup.+.
Step 3. Preparation of benzyl
1-isopropyl-1H-indol-5-ylcarbamate.
[0143] Benzyl chloroformate (0.670 mL, 0.0046 mol) is added
dropwise to a mixture 1-isopropyl-1H-indol-5-amine (0.68 g, 0.0039
mol) and pyridine (0.76 mL, 0.008 mol) in dichloromethane (20 mL)
at 0.degree. C. The mixture is stirred at 0.degree. C. for 30 min,
allowed to warm to room temperature and then diluted with water.
The organic layer is separated, washed with brine, dried
(Na.sub.2SO.sub.4) and evaporated to provide the title compound.
HPLC(SYMMETRY C.sub.18 3.5 .mu.M, 4.6.times.30 mm column; gradient
elution 2%-98% MeCN with 0.1% TFA over 10 min; 2 mL/min rate):
retention time=5.834 min; MS for C.sub.19H.sub.20N.sub.2O.sub.2
(m/z) 309.2 (M+H).sup.+.
Step 4. Preparation of
(R)-5-(hydroxymethyl)-3-(1-isopropyl-1H-indol-5-yl)oxazolidin-2-one.
[0144] Lithium bis(trimethylsilyl)amide (1M in THF, 35.7 mL, 0.036
mol) is added dropwise at -78.degree. C. to benzyl
1-isopropyl-1H-indol-5-ylcarbamate (5.5 g, 0.018 mol) in
tetrahydrofuran and the mixture stirred at that temperature for 30
minutes. R-Glycidyl butyrate (2.78 mL, 0.02 mol) is added and the
reaction allowed to warm to room temperature and stirred for 14 h.
The reaction is quenched with saturated aqueous ammonium chloride,
diluted with water and extracted with dichloromethane. The organic
layer is washed with brine, dried (Na.sub.2SO.sub.4) and
evaporated. The residue is purified by flash column chromatography
(20% ethyl acetate/hexane) to provide the title compound.
HPLC(SYMMETRY C.sub.18 3.5 .mu.M, 4.6.times.30 mm column; gradient
elution 2%-98% MeCN with 0.1% TFA over 10 min; 2 mL/min rate):
retention time=3.153 min; MS for C.sub.15H.sub.18N.sub.2O.sub.3
(m/z) 275.3 (M+H).sup.+.
Step 5. Preparation of
(R)-(3-(1-isopropyl-1H-indol-5-yl)-2-oxooxazolidin-5-yl)methyl
Methanesulfonate.
[0145] Methanesulfonyl chloride (0.84 g, 0.0073 mol) is added at
0.degree. C. to
(R)-5-hydroxymethyl)-3-(1-isopropyl-1H-indol-5-yl)oxazolidin-2-one
(2.0 g, 0.0073 mol) and triethylamine (1.52 mL, 0.011 mol) in
dichloromethane (25 mL) and stirred for 45 minutes. The reaction is
quenched with saturated sodium bicarbonate and extracted with
dichloromethane. The organic layer is washed with brine, dried
(Na.sub.2SO.sub.4) and evaporated to provide the title compound
suitable for use directly in the next step. HPLC (SYMMETRY C.sub.18
3.5 .mu.M, 4.6.times.30 mm column; gradient elution 2%-98% MECN
with 0.1% TFA over 10 min; 2 mL/min rate): retention time=5.04
min.
Step 6. Preparation of
(R)-5-azidomethyl)-3-(1-isopropyl-1H-indol-5-yl)oxazolidin-2-one.
[0146]
(R)-3-(1-Isopropyl-1H-indol-5-yl)-2-oxooxazolidin-5-yl)methyl
methanesulfonate (3.2 g, 0.0098 mol) and sodium azide (2.372 g,
0.036 mol) in dimethylformamide (15 mL) are heated at 70.degree. C.
for 16 h. The reaction is diluted with water and extracted with
dichloromethane. The organic layer is washed with brine, dried
(Na.sub.2SO.sub.4) and evaporated. The residue is purified by flash
column chromatography (20% ethyl acetate/hexane) to provide the
title compound. HPLC(SYMMETRY C.sub.18 3.5 .mu.M, 4.6.times.30 mm
column; gradient elution 2%-98% MeCN with 0.1% TFA over 10 min; 2
mL/min rate): retention time=5.429 min; MS for
C.sub.15H.sub.17N.sub.5O.sub.2 (m/z) 300.1 (M+H).sup.+.
Step 7. Preparation of
(R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(1-isopropyl-1H-indol-5-yl)oxazol-
idin-2-one.
[0147] Norbornadiene (1.948 mL, 0.018 mol) and
(R)-5-(azidomethyl)-3-(1-isopropyl-1H-indol-5-yl)oxazolidin-2-one
(2.7 g, 0.009 mol) in dioxane (20 mL) are heated at 70.degree. C.
for 14 h. The reaction is evaporated and the residue purified by
flash column chromatography (20% ethyl acetate/hexane) to provide
the title compound. HPLC(SYMMETRY C.sub.18 3.5 .mu.M, 4.6.times.30
mm column; gradient elution 2%-98% MeCN with 0.1% TFA over 10 min;
2 mL/min rate): retention time=4.556 min; MS for
C.sub.17H.sub.19N.sub.5O.sub.2 (m/z) 326.1 (M+H).sup.+.
Step 8. Preparation of
(R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(1-isopropyl-2-oxoindolin-5-yl)ox-
azolidin-2-one.
[0148] N-Bromosuccinimde (0.18 g, 0.001 mol) is added portion wise
to
(R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(1-isopropyl-1H-indol-5-yl)oxazol-
idin-2-one (0.32 g, 0.001 mol) in a 95:5 mixture of t-butanol and
water (3 mL) and stirred for 24 h. The reaction is filtered and the
solvent removed under reduced pressure. The residue is diluted with
water and extracted with dichloromethane. The organic layer is
washed with brine, dried (Na.sub.2SO.sub.4) and evaporated. The
residue is purified by PTLC (10% MeOH/DCM) to provide the title
compound. HPLC(SYMMETRY C.sub.18 3.5 .mu.M, 4.6.times.30 mm column;
gradient elution 2%-98% MeCN with 0.1% TFA over 10 min; 2 mL/min
rate): retention time=3.712 min; MS for
C.sub.17H.sub.19N.sub.5O.sub.3 (m/z) 342.1 (M+H).sup.+.
Method B
[0149] Step 1. Preparation of 1-isopropyl-1H-indole-2,3-dione.
[0150] 1H-Indole-2,3-dione (5.0 g, 0.034 mol), iodopropane (6.83
ml, 0.068 mol) and potassium carbonate (9.28 g, 0.068 mol) in DMF
(30 ml) are stirred at room temperature for 72 hours. The reaction
mixture is diluted with ethyl acetate, washed with water and brine,
dried (Na.sub.2SO.sub.4) and evaporated to provide the title
compound. HPLC r.t. 4.38 min; MS for C.sub.11H.sub.11NO.sub.2M/z
190.1 (M+H).sup.+.
Step 2. Preparation of 1-isopropyl-1,3-dihydro-indol-2-one.
[0151] 1-Isopropyl-1H-indole-2,3-dione (3.00 g, 15.9 mmol) was
heated with neat hydrazine hydrate (10 ml) at 130.degree. C. for
1.5 hours. The reaction was cooled, diluted with ice water, and
extracted with ethyl acetate. The organic layer is washed with
brine, dried (Na.sub.2SO.sub.4), and evaporated to provide the
title compound. HPLC r.t. 4.54 min; MS for C.sub.11H.sub.13NO m/z
176.1 (M+H).sup.+.
Step 3. Preparation of
1-isopropyl-5-nitro-1,3-dihydro-indol-2-one.
[0152] 1-Isopropyl-1,3-dihydro-indol-2-one (2.50 g, 14.3 mmol) is
added to a stirred solution of sodium nitrate (1.20 g, 14.26 mmol)
in trifluoroacetic acid (50 ml) and stirred at room temperature for
5 h. The reaction was diluted with ice water and resulting
precipitate filtered, washed with water, and dried under vacuum to
provide the title compound. HPLC r.t. 4.71 min; MS for
C.sub.11H.sub.12N.sub.2O.sub.3 m/z 219.0 (M-H).sup.-.
Step 4. Preparation of
5-amino-1-isopropyl-1,3-dihydro-indol-2-one.
[0153] Iron powder (2.63 g, 47.2 mmol) is added in small portion to
a mixture of 1-isopropyl-5-nitro-1,3-dihydro-indol-2-one (2.60 g,
11.8 mmol) and ammonium chloride (6.27 g, 118 mmol) in ethanol (80
ml) and water (40 ml) at 90.degree. C. The reaction mixture is
stirred vigorously and heated for 45 min, then cooled to room
temperature and diluted with dichloromethane (250 ml). The mixture
is filtered through celite, the organic layer separated and washed
with water and brine, dried (Na.sub.2SO.sub.4) and evaporated to
provide the title compound. HPLC r.t. 2.51 min; MS for
C.sub.11H.sub.14N.sub.2O m/z 191.1 (+M).sup.+.
Step 5. Preparation of
(R)-[2-hydroxy-3-(4-isopropyl-2-oxo-2,3-dihydro-1H-indol-5-ylamino)-propy-
l]-carbamic Acid tert-butyl Ester.
[0154] 5-Amino-1-isopropyl-1,34-dihydro-indol-2-one (0.76 g, 3.99
mmol), (S)-oxiranylmethyl-carbamic acid tert-butyl ester (0.69 g,
3.99 mmol) and lithium trifluoromethanesulfonate (0.617 g, 3.99
mmol) in acetonitrile (10 ml) is heated at 70.degree. C. for 2
hours. The reaction is diluted with ethyl acetate, washed with
water and brine, dried (Na.sub.2SO.sub.4) and evaporated. Final
purification by flash chromatography (20% Acetone/DCM) provide the
title compound. HPLC r.t. 3.61 min; MS for
C.sub.19H.sub.29N.sub.3O.sub.4 m/z 364.0 (M+1).sup.+.
Step 6. Preparation of
(S)-[3-(1-isopropyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-2-oxo-oxazolidin-5-y-
lmethyl]-carbamic Acid tert-butyl Ester.
[0155] Phosgene (20% solution in toluene, 0.602 ml, 6.18 mmol) is
added to
(5R)-[2-hydroxy-3-(1-isopropyl-2-oxo-2,3-dihydro-1H-indol-5-ylamino)-prop-
yl]-carbamic acid tert-butyl ester (0.15 g, 0.412 mmol) and
triethylamine (0.28 ml, 2.06 mmol) in dichloromethane (5 ml) at
0.degree. C. The reaction is allowed to warm to room temperature
and stirred for 2 h. The mixture is diluted with dichloromethane,
washed with water and brine, dried (Na.sub.2SO.sub.4) and
evaporated. Final purification by PTLC (5% MeOH/DCM) provides the
title compound. HPLC r.t. 4.78 min; MS for
C.sub.20H.sub.27N.sub.3O.sub.5 m/z 390.3 (M+H).sup.+.
Step 7. Preparation of
(R)-(5-aminomethyl-2-oxo-oxazolidin-3-yl)-1-isopropyl-1,3-dihydro-indole--
2-one
[0156]
(5R)-[3-Isopropyl-2-oxo-2,3-hydro-1H-indol-5-yl)-2-oxo-oxazolidin-5-
-ylmethyl]-carbamic acid tert-butyl ester (0.25 g, 0.642 mmol) is
treated with 50% TFA/DCM (4 ml) for 30 minutes at room temperature.
The reaction is evaporated to provide the title compound. HPLC r.t.
3.06 min; MS for C.sub.15H.sub.19N.sub.3O.sub.3 m/z 290.2
(M+H).sup.+.
Step 8. Preparation of
(R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-isopropyl-2-oxoindolin-5-yl)oxazo-
lidin-2-one.
[0157] Dichloroacetaldehyde (0.10 g, 0.0009 mol),
p-toluenesulfonhydrazide (0.16 g, 0.0009 mol) and acetic acid (0.02
mL, 0.0004 mol) in methanol (3 mL) are stirred at room temperature
for 1 h. The resulting white suspension of
N-(2,2-dichloroethylidene)-4-methylbenzenesulfonohydrazide is
cooled in an ice water bath and a mixture of
(S)-5-(aminomethyl)-3-(1-isopropyl-2-oxoindolin-5-yl)oxazolidin-2-one
(0.3 g, 0.0009 mol) and triethylamine (0.3 mL, 0.0018 mol) in
dimethylformamide (5 mL) added in one portion. The mixture is
stirred at room temperature overnight and the solvent removed under
reduced pressure. The residue is purified by PTLC (10%
methanol/dichloromethane) to provide the title compound.
HPLC(SYMMETRY C.sub.18 3.5 .mu.M, 4.6.times.30 mm column; gradient
elution 2%-98% MeCN with 0.1% TFA over 10 min; 2 mL/min rate):
retention time=3.709 min; .sup.1H NMR (300 MHz, DMSO-d.sub.6): 7.86
(d, J=2.2 Hz, 1H), 7.75 (d, J=2.2 Hz, 1H), 7.43 (s, 1H), 7.24 (d,
J=8.5 Hz, 1H), 7.01 (d, J=8.5 Hz, 1H), 5.06 (m, 1H), 4.86 (m, 1H),
4.73 (d, J=5.2 Hz, 2H), 4.58 (m, 2H), 4.19 (t, J=9.1 Hz, 1H), 3.82
(dd, J=5.8, 2.7 Hz, 1H), 3.56 (s, 2H), 1.57 (d, J=6.7 Hz, 6H); MS
for C.sub.17H.sub.19N.sub.5O.sub.3 (m/z) 342.1 (M+H).sup.+.
Example 2
Preparation of
(R)-5-(1H-1,2,3-triazol-1-yl)methyl)-3-(1-ethyl-2-oxoindolin-5-yl)oxazoli-
din-2-one
##STR00012##
[0159] Following the general procedure of Example 1, and making
non-critical variations but substituting iodoethane as starting
material (5.44 ml, 0.068 mol), the title compound is obtained. HPLC
(SYMMETRY C.sub.18 3.5 .mu.M, 4.6.times.30 mm column; gradient
elution 2%-98% MECN with 0.1% TFA over 10 min; 2 mL/min rate):
retention time=3.642 min; .sup.1H NMR (300 MHz, DMSO-d.sub.6): 7.87
(d, J=2.2 Hz, 1H), 7.74 (d, J=2.2 Hz, 1H), 7.43 (s, 1H), 7.24 (d,
J=8.5 Hz, 1H), 7.01 (d, J=8.5 Hz, 1H), 5.06 (m, 1H), 4.73 (d, J=5.2
Hz, 2H), 4.19 (t, J=9.1 Hz, 1H), 3.82 (dd, J=5.8, 2.7 Hz, 1H), 3.60
(m, 4H), 1.18 (t, J=6.7 Hz, 3H); MS for
C.sub.16H.sub.17N.sub.5O.sub.3 (m/z) 328.2 (M+H).sup.+.
* * * * *